GB2054370A

GB2054370A - Injectable potentiated sulphonamide compositions

Info

Publication number: GB2054370A
Application number: GB8001031A
Authority: GB
Original assignee: Rosco AS
Current assignee: Rosco AS
Priority date: 1979-07-24
Filing date: 1980-01-11
Publication date: 1981-02-18
Also published as: DK303580A; DE3026772A1; GB2054370B

Abstract

An injectable composition for veterinary use comprises an aqueous pH 6 to 8 solution of a salt, preferably the diethanolamine salt, of a sulphonamide, containing in suspension another sulphonamide and a potentiometer for sulphonamides, the content of dissolved sulphonamide being 3-40% w/v, the content of suspended sulphonamide being 3-40% w/v, the content of potentiator being 1-20% w/v, and the weight ratio of sulphonamides to potentiator being between 20:1 and 1:1, preferably 3:1. The dissolved sulphonamide may be sulphafurazole, sulphamethoxazole or sulphamoxide; suspended sulphonamides are sulphadimethoxine, sulphamethoxypyridazine, sulphadoxine, sulphadiazine or sulphamethoxydiazine. Potentiators are trimethoprim, diaveridine and ormethoprim.

Description

SPECIFICATION Injectable sulphonamide potentiator composition and its production The present invention relates to injectable veterinary compositions containing sulphonamide and potentiator, and to their production.

Potentiators enhance the therapeutic effect of sulphonamides.

Methods for the production of injectable sulphonamide potentiatorsolutions are known. Thus the U.S. patent 3,985,876, the U.K. patents 1,176,395 and 1,522,571,the Danish patents 137,434 and 137,594, and the German specification No. 2,627,706 all describe the preparation of sulphonamidepotentiator solutions, in which the active components are dissolved in organic solvents, the solutions all having a relatively small water content.

The German patent specifications Nos. 2,631,779 and 2,631,780 describe the preparation of sulphonamide - potentiator solutions with the aid of polyvinylpyrrolidone (20-80%1 resulting in preparations with a low content of active ingredients and a high viscosity.

A different method for the production of an injectable composition containing the said components is known from the Danish patent No. 128,229, describing the production of a suspension of the potentiator in an aqueous solution of the sodium salt of a sulphonamide, the said suspension having a pH value of 9.75 to 12.0.

Combinations of trimethoprim and sulphonamides have become widely used in the treatment of various infections in humans and in animals.

In the marketed compositions for use in human medicine, combinations of sulphonamides and potentiators (in the ratio 5:1) are chosen, having half-lives within the same range, half-life being defined as the time taken for the initial concentration in the blood of the active ingredients to decrease by 50%.

In animal medicine, however, there are some problems not taken into account in the known compositions which are on the market.

Thus, for example, large variations have been observed in the half-life of trimethoprim from one species to another, namely 9-12 hours in humans, 3 hours in dogs, 2 hours in pigs, 1 hour in cows, and 0.5 hour in goats. The same phenomenon has been observed with sulphonamides. For example, the half-life of sulfadoxine in pigs is 6.5 hours, in cows 11 hours, and in man 150-205 hours.

Further, Folke Ramussen et al (Research in Veterinary Science, 20,55-60, 1976) have demonstrated damage to muscle tissue in animals at the site of injection after intramuscular administration of the marketed trimethoprim - sulphonamide compositions prepared according to the Danish patent 128,229 and the British patent 1,176,395.

The damaging effect must be ascribed to a) the content of organic solvents in some of the compositions, and b)to the high pH value of all of the tested compositions.

The object of the present invention is to provide a stable injectable sulphonamide - potentiator composition for veterinary use which, notwithstanding the large differences in half-life of the active ingredients from species to species, can exhibit good antibacterial activity with less of the mentioned damage to the tissues at the injection site.

A composition according to the invention has a substantially neutral pH (pH 6-8) and comprises an aqueous solution of a (e.g. diethanolamine) salt of at least one sulphonamide containing in suspension particles of at least one other sulphonamide and of potentiator, the content of dissolved sulphonamide being 340% w/v, the content of suspended sulphonamide being 340% w/v, the content of potentiator being 1 -20% wN, and the weight ratio of total sulphonamide to potentiator being between 20:1 and 1:1; the total content of sulphonamides plus potentiator is preferably up to 60% w/v.

The injection of such a composition into domestic animals can result in long lasting serum concentrations of both sulphonamide and potentiator, because the suspended particles act as a reservoir, and may provide antimicrobial activity in the blood stream for 36 to 48 hours or more.

Sulphonamides for use in solution according to the invention are, for example, sulfafurazole (3,4 dimethyl - 5 - sulfanilamide - isoxazole), sulphamethoxazole (5 - methyl -3 - sulfanilamide isoxazole), and sulfamoxole (4, 5 - dimethyl - 2 - sulfanilamido - oxazole) salts, e.g. the diethanolamine salts.

Sulphonamides for use in suspension according to the invention are, for example, sulphadimethoxine (2,4 - dimethoxy - 6 - sulfanilamido - pyrimidine), sulphamethoxypyridazine (6 - methoxy - 3 - sulfanilamido - pyridazine), sulfadoxine (5, 6 dimethoxy - 3 - sulfanilamido - pyrimidine), sulphadiazine (2 -sulfanilylamido - pyrimidine), and sulphamethoxydiazine (2 - sulfanilamido - 5 methoxy - pyrimidine).

As potentiators of special value may be mentioned the 2,4 - diamino pyrimidine potentiators including trimethoprim (2,4 - diamino - 5 - (3,4, 5 5 -trimethox- ybenzyl) - pyrimidine), diaveridine (2,4 - diamino - 5 (3,4 - dimethoxybenzyl) - pyrimidine), and ormethoprim (2,4 - diamino - 5 - (2 - metnyl - 4, 5 dimethoxybenzyl) - pyrimidine).

Due to the aqueous nature of the solvent and to the neutral pH reaction, the compositions of the present invention after intramuscular injection tend to produce only a very slight reaction at the site of injection.

It has been surprisingly found that, although the pH value of the suspension compositions according to the invention is neutral (pH 6-8), the compositions are stable. No crystal growth or formation of complexes between the sulphonamides and the potentiator has been observed, even after long periods of storage. This is surprising, because according to the Danish patent 128,229 it is impossible to prepare stable suspensions of a dissolved sulphonamide salt and a suspended potentiator at a pH below 9.75.

After injection into animals of a composition according to the invention, the sulphonamide in solution provides a high initial blood concentration of sulphonamide, which is maintained in the therapeutical range, e.g. for48 hours, by the suspended sulphonamide.

The half-life of the potentiator is also increased significantly when in suspension, compared to its half-life in solution.

Due to the fact that the potentiator is rapidly metabolized by animals, we have found that the optimum ratio for most of the compositions according to the invention is 3 parts by weight of sulphonamides to 1 part by weight of potentiator, while in human medicine the optimum ratio for sulphonamide/trimethoprim compositions is 5:1.

In addition to the active ingredients mentioned hereinbefore, the injectable compositions of this invention may contain any of the various adjuvants, which are suitabiy used in the preparation of pharmaceutical suspensions. Thus, one may use, as optional ingredients, thickening agents, preservatives, stanilizers, wetting agents, buffers, and compounds for adjusting pH values. It should be understood, however, that these optional ingredients are given by way of example oniy, and that the invention is not restricted to the use thereof.

The invention also provides a process for preparing an injectable sulphonamide/potentiator composition which comprises dissolving at least one sulphonamide in the form of a water soluble salt in an aqueous solvent, and milling a suspension of at least one other sulphonamide and potentiator in the solution. The water soluble sulphonamide salt, prefer ably the diethanolamine salt, is conveniently formed in situ; the milling is generally conducted until the size of the majority of the suspended particles is less than 10 microns.

The composition and method according to the invention are illustrated by the following specific Examples.

Example 1 The following ingredients were used: Sulphafurazole 409 Diethanolamine 15.79 Sulphadimethoxine 209 Trimethoprim 209 Lecithin 0.89 Sodium formaldehyde sulfoxylate 0.29 Polyvinylpyrrolidone 5g Benzyl Alcohol 29 Water for Injection to 200ml Sulphafurazole and diethanolamine are dissolved in 80 ml of water for injection. Thereafter, the polyvinylpyrrolidone is dissolved, and the solution is sterilized by filtration.

Lecithin and sodium formaldehyde sulfoxylate are dissolved in 50 ml of water for injection and sterilized at 121 C for 20 minutes. After cooling, the two sterile solutions are mixed in a sterile vessel, the pH value being 7.45.

While stirring, sterile sulphadimethoxine and trimethoprim, as well as benzyl alcohol are added aseptically, and the mixture with added water to a final volume of200 ml is milled in a pre-sterilized ball mill until the majority of particles are below 10 mic rons. The final suspension has a total content of 30% of sulphonamide and 10% of potentiator, a pH value of 7.50, and a viscosity (Emila viscosimeter) of 16 cps at 20 C.

When injected intramuscularly into rabbits at the rate of 30 mg/kg, therapeutically effective sulphonamide and trimethoprim blood levels were observed for more than 48 hours after the injection.

Example 2 Sulphafurazole 189 Diethanolamine 7.19 Sulphadimethoxine 129 Diaveridine 6g Lecithin 0.49 Sodium metabisulphite 0.19 Benzyl Alcohol 1g Polyvinylpyrrolidone 2.59 Waterforlnjection to 100 ml The procedure mentioned in Example 1 was followed, using diaveridine instead oftrimethoprim, and sodium metabisulphite instead of sodium formaldehyde sulfoxylate.

The final suspension has a total content of 30% of sulphonamide and 6% of potentiator, a pH value of 7.29, and a viscosity of 10 cps at 200C. The preparation shows, after injection into domestic animals, therapeutically effective blood levels of both sulphonamide and potentiator, lasting more than 36 hours.

Example 3 Sulphafurazole 50g Diethanolamine 19.6g Sulphadiazine 259 Trimethoprim 259 Lecithin 1,09 Sodium formaldehyde sulfoxylate 0.29 Benzvl Alcohol 29 Disodium phosphate 39 Water four injection to 200 ml The procedure mentioned in Example 1 was followed, using sulphadiazine instead of sulphadimethoxine and disodium phosphate instead of polyvinylpyrrolidone.

The final suspension has a total content of 37.5% of sulphonamide and 12.5% of potentiator, a pH value of 7.82, and a viscosity of 13 cps at 20"C.

Example 4 The procedure of Example 1 was repeated, using sulphamethoxydiazine instead of sulphadiazine in equivalent amounts.

The final suspension has a total content of 37.5% of sulphonamide and 12.5% of potentiator, a pH value of 7.65, and a viscosity of 12 cps at 20"C.

The compositions of Examples 3 and 4 give therapeutically effective blood levels of sui- phonamide and potentiator for more than 36 hours after being injected into domestic animals.

Claims

1. An injectable, aqueous sulphonamide/potentiator composition which has a pH of 6.0 to 8.0 and comprises a salt of at least one sulphonamide containing in suspension particles of at least one other sulphonamide and of potentiator, the content of dissolved sulphonamide being 340% w/v, the content of suspended sulphonamide being 340% w/v, the content of potentiator being 1-20% w/v, and the weight ratio of total sulphonamide to potentiator being between 20:1 and 1:1.

2. A composition according to claim 1 wherein the total content of sulphonamides plus potentiator is up to 60% w/v.

3. A composition according to claim 1 or 2 in which the weight ratio of sulphonamides to poten tiatoris3:1.

4. A composition according to claim 1,2 or 3 containing dissolved sulphafurazole, suspended sulphadimethoxine, and trimethoprim or diaveridine potentiator.

5. A composition according to claim 1,2 or3 containing dissolved sulphafurazole, suspended sulphadiazine or sulphamethoxydiazine, and trimethoprim potentiator.

6. A composition according to any preceding claim wherein the dissolved sulphonamide salt is the diethanolamine salt.

6. Acomposition according to any preceding claim wherein the dissolved sulphonamide salt is the ethanolamine salt.

7. An injectable sulphonamide/potentiator com- position substantially as hereinbefore described in any of Examples 1 to 4.

8. A process for preparing an injectable sul phonamidelpotentiator composition according to claim 1 which comprises dissolving at least one sulphonamide in the form of a water soluble salt in an aqueous solvent, and milling a suspension of at least one other sulphonamide and potentiator in the solution.

9. A method according to claim 8 wherein the water soluble sulphonamide salt is the diethanolamine salt.

10. A method according to claim 8 or 9 wherein the sulphonamide salt is formed in situ.

11. A method according to any of claims 8 to 10 wherein the suspension is milled until the size of the majority of the suspended particles is below 10 microns.

12. Amethod of preparing an injectable sul phonamidelpotentiator composition, the method being substantially as hereinbefore described in any of Examples 1 to 4.

New claims or amendments to claims filed on 18.9.80.

Superseded claims: 1 and 6.

New or amended claims:

1. An injectable, aqueous sulphonamide/potentiator composition which has a pH of 6.0 to 8.0 and comprises an aqueous solution of a salt of at least one sulphonamide containing in suspension particles of at least one other sulphonamide and of potentiator, the content of dissolved sulphonamide being 340% w/v, the content of suspended sulphonamide being 340% w/v, the content of potentiator being 1-20% w/v, and the weight ratio of total sulphonamide to potentiator being between 20:1 and 1:1.